Successful application of gene therapy for treatment of human disease requires the efficient and safe delivery of therapeutic genes to the desired sites of expression. The most effective approach would be to develop vectors that home to and transduce specific cells and tissues through an intravenous route. Towards this end, we made significant progress in developing oncoretroviral and lentiviral vectors, in combination with pseudotypes of Sindbis virus envelope, for stable transduction of genes delivered via the bloodstream.The central hypothesis of this proposal is that efficient targeting vectors with high selectivity can be developed based upon oncoretroviral and lentiviral vectors. Numerous previous efforts have been made to develop retroviral vectors that can target specific cells and tissues. Typically, this involved modification of the native envelope and/or pseudotyping with other viral envelopes. These approaches have not been generally applicable because modifications in native envelope lead to large reductions in viral titer and pseudotypes with other viral envelopes are not generally applicable to targeting of many different types of cells and tissues. In 2001 we reported the use of a modified Sindbis virus envelope bearing the Fc binding domain of protein A to pseudotype retroviral vectors and redirect their specificity with monoclonal antibodies. Recently, we reported further modifications to enable the targeting to cells and tissues in living animals through intravenous injection. We propose to further characterize the properties of this vector in regards to its virological properties and utilize such information for further development of vector specificity and efficiency of targeting in living animals. Given our long-standing interest in retroviral biology, recent development of gene therapy vectors and studies in mice and non-human primates, we feel that we are well positioned to address the questions posed in this application.